Hetrocyclic aryl sulphonamides

ABSTRACT

The invention relates to novel sulfonamides of general formula (I) 
                         
where the substituents R 1 , R 2 , R 3 , R 4 , A and X have the given meanings, pharmaceutical compositions containing them, and a method of using them as antiviral agents, in particular against cytomegaloviruses.

The present invention relates to new compounds, processes for theirpreparation and their use as medicaments, in particular as antiviralagents, in particular against cytomegaloviruses.

The compound2,2-dimethyl-N-[4-[[[4-(4-phenyl-2H-1,2,3-triazol-2-yl)phenyl]-sulphonyl]amino]phenyl]-propanamideis known as having antiviral activity from WO 99/37291.

It is an object of the present invention to make available alternativeagents or agents having better activity against cytomegaloviruses.

The present invention relates to compounds of the general formula (I)

in which

-   R² and R³ are identical or different and represent hydrogen,    hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,    (C₁–C₆)-alkyl, (C₁–C₆)-alkoxy or a group of the formula

-    in which    -   R⁵, R⁶ and R⁷ are identical or different and in each case        represent hydrogen or (C₁–C₆)-alkyl, which for its part can be        substituted by one or two substituents, selected from the group        consisting of hydroxyl, halogen, cyano, trifluoromethyl and        trifluoromethoxy,-   A represents five- or six-membered heteroaryl linked via a C atom to    the adjacent phenyl ring,-   R¹ represents the radical

-    in which    -   R¹¹ represents the side group of an amino acid, and the amino        group in R¹ can optionally be mono- or polysubstituted by        (C₁–C₆)alkyl, alkylcarbonyl, phenyl,        or-   R¹ represents a straight-chain or branched (C₁–C₅)-alkyl radical,    which for its part can be substituted by one or more groups selected    from phenyl, piperidinyl, pyridinyl, thiazolyl, thienyl,

-    a group

-    in which    -   R¹² and R¹³ are identical or different and can represent        hydrogen, (C₁–C₆)alkyl, alkylcarbonyl, an amino protective        group, phenyl,    -   or    -   R¹ represents a radical

-   -    or    -   R¹ represents a straight-chain or branched (C₁–C₅)-alkyl        radical, which for its part is substituted by a group

-   -    in which        -   R¹⁴, R¹⁵, R¹⁶ are identical or different and represent            hydrogen or (C₁–C₆)alkyl        -   and        -   n can assume the values 2 or 3,            or

-   R¹ represents piperidinyl or the radical

-    in which R¹² and R¹³ have the meaning indicated above,-   n represents a number from 1 to 4 and the ring can be up to    trisubstituted in an identical or different manner by halogen,    (C₁–C₆)-alkyl, halogeno-(C₁–C₆)-alkyl, amino, hydroxyl,-   R⁴ represents tert-butyl, which is optionally up to trisubstituted,    in an identical or different manner, by hydroxyl, fluorine or    chlorine, or-    represents cyclopropyl or cyclobutyl, which are mono- to    trisubstituted in an identical or independent manner by halogen or    (C₁–C₆)-alkyl, (C₁–C₆)-alkyl being optionally substituted by    hydroxyl, fluorine or chlorine,    and in which-   X represents oxygen or sulphur,    and in which nitrogen-containing heterocycles can also be present as    N-oxides,    and their tautomers, stereoisomers, stereoisomeric mixtures and    their pharmacologically tolerable salts.

(C₁–C₆)-Alkyl in the context of the invention represents astraight-chain or branched alkyl radical having 1 to 6 carbon atoms.Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, n-pentyl and n-hexyl.

(C₁–C₆)-Cycloalkyl in the context of the invention represents acycloalkyl group having 3 to 6 carbon atoms. Examples which may bementioned are: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

(C₃–C₆)-Alkoxy in the context of the invention represents astraight-chain or branched alkoxy radical having 1 to 6 carbon atoms.Examples which may be mentioned are: methoxy, ethoxy, n-propoxy,isopropoxy, t-butoxy, n-pentoxy and n-hexoxy. Methoxy and ethoxy arepreferred.

(C₆–C₁₀)-Aryl in the context of the invention represents an aromaticradical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyland naphthyl.

Aralkyl in the context of the invention represents (C₆–C₁₀)-aryl, whichfor its part is bonded to (C₁–C₄)alkyl. Benzyl is preferred.

Mono-(C₁–C₆)-alkylamino in the context of the invention represents anamino group having a straight-chain, branched or cyclic alkylsubstituent which contains 1 to 6 carbon atoms. Examples which may bementioned are: methylamino, ethylamino, n-propylamino, isopropylamino,cyclopropylamino, t-butylamino, n-pentylamino, cyclopentylamino andn-hexylamino.

Di-(C₁–C₆)-alkylamino in the context of the invention represents anamino group having two identical or different straight-chain, branchedor cyclic alkyl substituents, which in each case contain 1 to 6 carbonatoms. Examples which may be mentioned are: N,N-dimethylamino,N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino,N-methyl-N-cyclopropylamino, N-isopropyl-N-n-propylamino,N-t-butyl-N-methylamino, N-ethyl-N-n-pentylamino andN-n-hexyl-N-methylamino.

Heteroaryl in the context of the invention represents a monocyclicheteroaromatic having up to 3 heteroatoms from the group consisting ofS, N and/or O, which is linked via a ring carbon atom of theheteroaromatic, optionally also via a ring nitrogen atom of theheteroaromatic. Examples which may be mentioned are: furan-2-yl,furan-3-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, thienyl, thiazolyl,oxazolyl, imidazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl.Oxadiazolyl, thiadiazolyl are preferred.

Halogen in the context of the invention in general represents fluorine,chlorine, bromine and iodine. Fluorine, chlorine and bromine arepreferred. Fluorine and chlorine are particularly preferred.

A 3- or 5-linked 1,2,4-oxadiazole represents an oxadiazole which isbonded to the phenylsulphonamide via the 3- or 5- ring carbon atom.

The side group of an amino acid is understood in the context of theinvention as meaning, for example, hydrogen (glycine), methyl (alanine),propan-2-yl (valine), 2-methyl-propan-1-yl (leucine),1-methyl-propan-1-yl (isoleucine), a propane-1,3-diyl group which isbonded to the nitrogen atom of the amino group (proline), a2-hydroxy-propan-1,3-diyl-group which is bonded to the nitrogen atom ofthe amino group (hydroxyproline), a group of the formula

(tryptophan), a benzyl group (phenylalanine), a methylthioethyl group(methionine), hydroxymethyl (serine), p-hydroxybenzyl (tyrosine),1-hydroxyl-ethan-1-yl (threonine), mercaptomethyl (cysteine),carbamoylmethyl (asparagine), carbamoylethyl (glutamine), carboxymethyl(aspartic acid), carboxyethyl (glutamic acid), 4-aminobutan-1-yl(lysine), 3-guanidinopropan-1-yl (arginine), imidazol-4-ylmethyl(histidine), 3-ureidopropan-1-yl (citrulline), mercaptoethyl(homocysteine), hydroxyethyl (homoserine), 4-amino-3-hydroxybutan-1-yl(hydroxylysine), 3-amino-propan-1-yl (ornithine).

Amino protective group in the context of the present inventionrepresents a protective group which makes the amino group insensitive tosome reaction conditions, but which can be removed again simply underother reaction conditions, see T. W. Greene, P. G. Wuts, ProtectiveGroups in Organic Synthesis, 3^(rd) ed., John Wiley, New York, 1999.Preferred amino protective groups are carbamates, e.g.tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (FMOC) orbenzyloxy-carbonyl (Cbz-/Z-) or other oxycarbonyl derivatives.

Preferred salts in the context of the invention are physiologicallyacceptable salts of the compounds according to the invention.

Physiologically acceptable salts of the compounds according to theinvention can be acid addition salts of the substances according to theinvention with mineral acids, carboxylic acids or sulphonic acids.Particularly preferred salts are, for example, those with hydrochloricacid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid,benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid,trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, citricacid, fumaric acid, maleic acid or benzoic acid.

Salts which can be mentioned are, however, also salts with customarybases, such as, for example, alkali metal salts (e.g. sodium orpotassium salts), alkaline earth metal salts (e.g. calcium or magnesiumsalts) or ammonium salts, derived from ammonia or organic amines suchas, for example, diethylamine, triethylamine, ethyldiisopropyl-amine,procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine,1-ephenamine or methylpiperidine, or derived from natural amino acidssuch as, for example, glycine, lysine, arginine or histidine.

The compounds according to the invention can exist in stereoisomericforms, which either behave as image and mirror image (enantiomers), orwhich do not behave as image and mirror image (diastereomers). Theinvention relates both to the enantiomers or diastereomers and to theirrespective mixtures. The racemic forms, just like the diastereomers, canbe separated into the stereoisomerically uniform constituents in a knownmanner.

Moreover, the invention also comprises prodrugs of the compoundsaccording to the invention. “Prodrugs” are designated according to theinvention as those derivatives of the compounds of the general formula(I) which can be biologically less active or even inactive themselves,but after administration are converted into the correspondingbiologically active form under physiological conditions (for examplemetabolically, solvolytically or in another manner).

The abovementioned radical definitions, which are general or indicatedin preferred ranges apply to the final products of the formula (I) andalso correspondingly to the starting substances or intermediates neededin each case for preparation.

The radical definitions specifically indicated in the respectivecombinations or preferred combinations of radicals are arbitrarily alsoreplaced by radical definitions of other combinations independently ofthe combinations of the radicals respectively indicated.

The invention preferably relates to compounds of the general formula(I),

in which

-   R² and R³ are identical or different and represent hydrogen or    halogen,-   A represents the radical (A-I)

-    which is linked via one of the carbon atoms of positions 3 or 5 to    the adjacent phenyl ring,-    and in which    -   Y represents oxygen,        or-   A represents the radical (A-II)

-    which is linked via one of the carbon atoms of positions 2 or 5 to    the adjacent phenyl ring,-    and in which    -   Y represents oxygen,-   R¹ represents the radical

-    in which    -   R¹¹ represents the side group of an amino acid, and the amino        group in R¹ can optionally be mono- or polysubstituted by        (C₁–C₆)-alkyl, alkylcarbonyl, an amino protective group, phenyl,        or-   R¹ represents a straight-chain or branched (C₁–C₅)-alkyl radical,    which for its part can be substituted by one or more groups selected    from phenyl, piperidinyl, pyridinyl, thiazolyl, thienyl,

-    a group

-    in which    -   R¹² and R¹³ are identical or different and can represent        hydrogen, (C₁–C₆)-alkyl, alkylcarbonyl, an amino protective        group, phenyl,    -   or    -   R¹ represents a straight-chain or branched (C₁–C₅)-alkyl        radical, which for its part is substituted by a group

-   -    in which        -   R¹⁴, R¹⁵, R¹⁶ are identical or different and represent            hydrogen or methyl        -   and        -   n can assume the values 2 or 3,            or

-   R¹ represents piperidin-3-yl or the radical

-   R⁴ represents tert-butyl, which is optionally up to trisubstituted,    in an identical or different manner, by hydroxyl, fluorine or    chlorine, or-    represents cyclopropyl or cyclobutyl, which is substituted in the    α-position to the carbonyl group or thiocarbonyl group by methyl,    which for its part is optionally substituted by hydroxyl, fluorine    or chlorine,    and in which-   X represents oxygen,    and in which nitrogen-containing heterocycles can also be present as    N-oxides,    and their tautomers, stereoisomers, stereoisomeric mixtures and    their pharmacologically tolerable salts.

The invention relates particularly preferably to compounds of thegeneral formula (I),

in which

-   R² and R³ represent hydrogen,-   A represents one of the radicals

-   R¹ represents the radical

-    in which    -   R¹¹ represents the side group of an amino acid, and the amino        group in R¹ can optionally be mono- or polysubstituted by        methyl, alkylcarbonyl, an amino protective group, phenyl,        or-   R¹ represents a straight-chain or branched (C₁–C₅)-alkyl radical,    which for its part can be substituted by one or more groups selected    from phenyl, piperidinyl, pyridinyl, thiazolyl, thienyl,

-    a group

-    in which    -   R¹² and R¹³ are identical or different and can represent        hydrogen, methyl, alkylcarbonyl, an amino protective group,        phenyl,    -   or    -   R¹ represents a straight-chain or branched (C₁–C₅) alkyl        radical, which for its part is substituted by a group

-   -    in which        -   R¹⁴, R¹⁵, R¹⁶ are identical or different and represent            hydrogen or methyl        -   and        -   n can assume the values 2 or 3,            or

-   R¹ represents piperidin-3-yl or the radical

-   R⁴ represents tert-butyl, which is optionally up to trisubstituted,    in an identical or different manner, by hydroxyl, fluorine or    chlorine, or-    represents cyclopropyl or cyclobutyl, which is substituted in the    α- position to the carbonyl group or thiocarbonyl group by methyl,    which for its part is optionally substituted by hydroxyl, fluorine    or chlorine,    and in which-   X represents oxygen,    and in which nitrogen-containing heterocycles can also be present as    N-oxides,    and their tautomers, stereoisomers, stereoisomeric mixtures and    their pharmacologically tolerable salts.

In a preferred embodiment, the invention relates to compounds of thegeneral formula (Ia)

in which

-   R¹, R², R³, R⁴, A and X have the meanings indicated above.

In a further preferred embodiment, the invention relates to thosecompounds of the general formula (I),

in which

-   R⁴ represents one of the radicals

In a further preferred embodiment, the invention relates to thosecompounds of the general formula (I),

in which

-   A represents a 3-linked 1,2,4-oxadiazole.

Very particularly preferred compounds of the present invention aresulphonamides which are selected from the group consisting of thefollowing compounds:

The invention further relates to processes for the preparation ofcompounds of the general formula (I), characterized in that

-   [A] nitro-anilines of the general formula [A-1]

in which

-   R³ has the meaning indicated above,    are reacted with compounds of the general formula [A-2]

in which

-   X and R⁴ have one of the meanings indicated above,    and-   Q represents a leaving group, e.g. halogen, preferably chlorine or    bromine,-   in inert solvents in the presence of a base to give compounds of the    general formula [A-3]

in which

-   X, R³ and R⁴ have one of the meanings indicated above,    and-   [B] the nitro-aromatics of the general formula [A-3] are reduced,    for example in the presence of transition metal catalysts and    hydrogen, in inert solvents to give aromatic amines of the general    formula [B-1]

in which

-   X, R³ and R⁴ have one of the meanings indicated above,    and-   [C] amines of the general formula [B-1] are reacted with sulphonic    acid derivatives of the general formula [C-1]

in which

-   R² has the meaning indicated above,    and-   Z represents a leaving group, e.g. halogen, preferably chlorine or    bromine,    in inert solvents, in the presence of a base, to give compounds of    the general formula [C-2]

in which

-   X, R², R³ and R⁴ have one of the meanings indicated above,    and-   [D] the nitriles of the general formula [C-2] are reacted in polar    protic solvents, for example alcohols, at elevated temperature,    preferably the boiling temperature of the solvent, in presence of a    base with hydroxylamine to give amidoximes of the general formula    [D-1]

in which

-   X, R², R³ and R⁴ have one of the meanings indicated above,    and-   [E] amidoximes of the general formula [D-1] are acylated with a    carboxylic acid of the general formula [E-1]    R′—COOH  [E-1]    in which-   R¹ has the meaning indicated above and amino groups contained in R¹    are present in protected form with protective groups known from    peptide chemistry, such as, for example, the Boc protective group,    in the presence of a condensing agent, for example    benzotriazolyl-N-oxy-tris(dimethylamino)phosphonium    hexafluorophosphate (PyBOP), or other activating reagents and acid    chlorides known from peptide chemistry, and a base in a polar,    aprotic solvent, for example tetrahydrofuran, the acylated amidoxime    is isolated as a crude product and subsequently cyclized to the    1,2,4-oxadiazole in a high-boiling, polar solvent, for example DMF,    at elevated temperature.

The process according to the invention for the preparation of1,2,4-oxadiazoles linked via position 3 is illustrated by way of exampleby the following reaction scheme:

The invention further relates to processes for the preparation ofcompounds of the general formula (I), characterized in that

-   [F] sulphonyl halides of the general formula [F-1]

in which

-   R² and Z have the meaning indicated above,    and-   R^(F-1) represents (C₁–C₄)-alkyl, aralkyl or a carboxylic acid    protective group,    are reacted in the presence of a base with anilines of the general    formula [B-1] to give sulphonamides of the general formula [F-2]

in which

-   R^(F-1), R², R³, R⁴ and X have the meaning indicated above,    and subsequently the group R^(F-1) is removed from the compounds of    the general formula [F-2], for example in the presence of hydroxyl    anions, and reacted to give sulphonamides of the general formula    [F-3],

and

-   [G] amid-oximes of the general formula [G-1]

in which

-   R¹ has the meaning indicated above,    are condensed with compounds of the general formula [F-3] to give    compounds of the general formula [G-2],

in which

-   R¹, R², R³, R⁴ and X have the meaning indicated above,    and-   [H] compounds of the general formula [G-2] are cyclized thermally to    the 5-linked 1,2,4-oxadiazoles of the general formula [H-1]    according to the invention

in which

-   R¹, R², R³, R⁴ and X have the meaning indicated above.

The process according to the invention is illustrated by way of exampleby the following reaction schemes:

Suitable solvents for all process steps are the customary inertsolvents, which do not change under the reaction conditions. Thesepreferably include organic solvents such as ethers, e.g. diethyl ether,glycol mono- or dimethyl ether, dioxane or tetrahydrofuran, or alcoholssuch as methanol, ethanol, n-propanol, iso-propanol, n-butanol ortert-butanol, or hydrocarbons such as benzene, toluene, xylene,cyclohexane or petroleum fractions or halogenohydrocarbons such asmethylene chloride, chloroform, carbon tetrachloride, or dimethylsulphoxide, dimethylform-amide, hexamethylphosphoramide, ethyl acetate,pyridine, triethylamine or picoline. It is likewise possible to usemixtures of the solvents mentioned, optionally also with water.Methylene chloride, tetrahydrofuran, dioxane and dioxane/water and inparticular the solvents mentioned in the section of the text “Generalworking procedures” are particularly preferred.

Suitable bases are organic amines such as tri-(C₁–C₆)-alkylamines, forexample triethylamine, or heterocycles such as pyridine,methylpiperidine, piperidine or N-methylmorpholine. Triethylamine andpyridine are preferred.

The bases are in general employed in an amount from 0.1 mol to 5 mol,preferably from 1 mol to 3 mol, in each case based on 1 mol of thecompounds of the general formulae [A-1], [B-1], [C-2], [D-1] and [E-1].

Suitable carboxylic acid protective groups are those which make thecarboxylic acid group insensitive to certain reaction conditions, butwhich can be simply removed again under other reaction conditions, seeT. W. Greene, P. G. Wuts, Protective Groups in Organic Synthesis, 3^(rd)ed., John Wiley, New York, 1999. Preferred carboxylic acid protectivegroups are esters such as alkyl esters or aralkyl esters, in particularbenzyl esters and benzyl derivatives.

The reactions can be carried out at normal pressure, but also atelevated or reduced pressure (e.g. 0.5 to 3 bar). In general, they arecarried out at normal pressure.

The reactions are carried out in a temperature range from 0° C. to 150°C., preferably at 0° C. to 30° C. and at normal pressure. The reactionof the compounds [G-2] to [H-1] is carried out at elevated temperature,preferably at temperatures above 100° C.

The reductions can in general be carried out by means of hydrogen ininert organic solvents such as dimethylformamide, alcohols, ethers oresters of acetic acid, or their mixtures, using catalysts such as Raneynickel, palladium, palladium on carbon or platinum, or using hydrides orboranes, or using inorganic reducing agents such as, for example,tin(II) chloride, in inert solvents, optionally in the presence of acatalyst. Palladium on carbon is preferred.

The reaction can be carried out at normal or at elevated pressure (e.g.1 to 5 bar). In general, it is carried out at normal pressure.Hydrogenations are preferably carried out under elevated pressure, ingeneral at 3 bar.

The reductions are in general carried out in a temperature range from 0°C. to +60° C., preferably at +10° C. to +40° C.

Suitable solvents for the acylation are customary organic solvents,which do not change under the reaction conditions. These preferablyinclude ethers such as diethyl ether, dioxane, tetrahydrofuran, glycoldimethyl ether, or hydrocarbons such as benzene, toluene, xylene,hexane, cyclohexane or petroleum fractions, or halogeno-hydrocarbonssuch as dichloromethane, trichloromethane, tetrachloromethane,dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate,or triethylamine, pyridine, dimethylformamide, acetonitrile or acetone.It is likewise possible to use mixtures of the solvents mentioned.Dichlormethane, tetrahydrofuran and pyridine are preferred.

The acylation is carried out in the abovementioned solvents attemperatures from 0° C. to +150° C., preferably at room temperature to+100° C. and at normal pressure.

The compounds of the general formulae [A-1], [A-2], [C-1], [E-1], [F-1]and [G-1] are known per se or can be prepared by methods known from theliterature.

Further compounds of the general formula (I), in which A represents a1,3,4-oxadiazole, can be prepared, for example, according to Scheme 4 asgiven below on a polymeric support, e.g. formyl resin (from Nova), 0.78mmol/g, called “formyl resin” below, using the IRORI system according tothe “Split & Mix” method:

The processes shown according to Scheme 4 thus allow the preparation offurther compounds of the general formula (I) according to the invention,in which

-   X represents oxygen    and-   A represents the radical (A-II)

-    which is linked to the adjacent phenyl ring via one of the carbon    atoms of positions 2 or 5,-    and in which-   Y represents oxygen,    by cyclizing hydrazides of the general formula [H-2]

in which X, R¹, R², R³, R⁴ have one of the meanings indicated above,and

-   FH represents hydrogen, an amino protective group or a polymeric    support,    with removal of water to give the compounds of the general formula    (I).

The compounds of the general formula (I) according to the invention havean unforeseeable surprising spectrum of action. They have an antiviralaction against representatives of the group consisting of Herpesviridae, particularly against human cytomegalovirus (HCMV). They arethus suitable for the treatment and prophylaxis of diseases which arecaused by Herpes viridae, in particular of diseases which are caused byhuman cytomegaloviruses.

The compounds of the general formula (I) can be used on account of theirparticular properties for the production of medicaments which aresuitable for the prophylaxis or treatment of illnesses, in particularviral diseases.

On account of their properties, the compounds according to the inventionare valuable active compounds for the treatment and prophylaxis of humancytomegalovirus infections and diseases caused thereby. Indication areaswhich can be mentioned are, for example:

-   1) Treatment and prophylaxis of HCMV infections in AIDS patients    (retinitis, pneumonitis, gastrointestinal infections).-   2) Treatment and prophylaxis of cytomegalovirus infections in bone    marrow and organ transplantation patients who are suffering, often    in a life-threatening manner, from HCMV pneumonitis, HCMV    encephalitis, and also from gastrointestinal and systemic HCMV    infections.-   3) Treatment and prophylaxis of HCMV infections in newborn children    and infants.-   4) Treatment of an acute HCMV infection in pregnant women.-   5) Treatment of HCMV infection in immunosuppressed patients in    cancer and cancer therapy.

The new active compounds can be employed on their own and, if required,also in combination with other antiviral active compounds such as, forexample, gancyclovir or acyclovir.

Biological Test Descriptions:

In vitro Action:

Anti-HCMV (anti-human cytomegalovirus) and anti-MCMV (anti-murinecytomegalovirus) cytopathogenicity tests:

The test compounds were employed as 50 millimolar (mM) solutions indimethyl sulfoxide (DMSO). Ganciclovir, foscarnet and cidofovir servedas reference compounds. After the addition of 2 μl in each case of the50, 5, 0.5 and 0.05 mM DMSO stock solutions to 98 μl each of cellculture medium in row 2 A-H in duplicate, 1:2 dilutions using 50 μl eachof medium up to row 11 of the 96-well plate were carried out. The wellsin rows 1 and 12 each contained 50 μl of medium. 150 μl each of asuspension of 1×10⁴ cells (human lung fibroblasts [HELF]) were thenpipetted into the wells (row 1=cell control) or a mixture ofHCMV-infected and non-infected HELF cells (M.O.I.=0.001–0.002), i.e. 1–2infected cells to 1000 non-infected cells, was pipetted into rows 2–12.Row 12 (without substance) served as a virus control. The final testconcentrations were 250–0.0005 μM. The plates were incubated at 37°C./5% CO₂ for 6 days, i.e. until all cells were infected in the viruscontrols (100% cytopathogenic effect [CPE]). The wells were then fixedby addition of a mixture of formalin and Giemsa's stain and stained (30minutes), washed with double-distilled water and dried at 50° C. in adrying oven. The plates were then evaluated visually using an overheadmicroscope (Plaque multiplier from Technomara).

It was possible to determine the following data from the test plates:

-   -   EC₅₀ (HCMV)=substance concentration in μM which inhibited the        CPE (cytopathic effect) by 50% in comparison to the untreated        virus control;    -   SI (selectivity index)=CC₅₀ (HELF)/EC₅₀ (HCMV).

The anti-MCMV test was carried out in a modification of the processdescribed above for HCMV with the following changes: A cell-free virussuspension was mixed with a concentrated cell suspension (3T3 mousecells) and incubated for 15 minutes for the adsorption of the viruses,before it was diluted to 1.3×10⁵ cells/ml with medium with an endmultiplicity of infection (M.O.I.) of 0.05–0.1 and distributed into thewells using 150 μl each. The incubation time was 5 days.

Representative activity data for the compounds according to theinvention are presented in Table 1:

TABLE 1 HELF HCMV 3T3 MCMV Example CC₅₀ EC₅₀ SI CC₅₀ EC₅₀ SI No. [μM][μM] HCMV [μM] [μM] MCMV 1 >250 0.028 >8929 18 0.035 514 2 118 0.35 3372.5 0.05 50 3 >250 0.074 3378 63 0.074 851In vivo Action:MCMV Mortality Test:Animals:

2–3 week-old female immunocompetent mice (12–14 g), strain Balb/C AnN orCD1 were obtained from commercial breeders (Bomholtgaard, Iffa, Credo).The animals were not kept under sterile conditions.

Virus Growth:

Murine cytomegalovirus (MCMV), strain Smith, was repeatedly passaged infemale CD1 mice in vivo. 21 days after intraperitoneal infection (2×10⁴plaque forming units/0.2 ml/mouse), the salivary glands were removed,taken up in a three-fold volume of Minimal Essential Medium (MEM)+10%foetal calf serum (FCS) and homogenized with the aid of an Ultraturrax.10% DMSO v/v was added, 1 ml aliquots were prepared and the virussuspension was stored at −140° C. After serial dilution of the salivarygland isolate in steps of ten, the titre determination was carried outin cell culture on NIH 3T3 cells after staining with Giemsa solution,and the determination of the lethal dose in vivo was carried out in 2–3week-old Balb/C mice.

Virus Infection of the Experimental Animals Treatment and Evaluation:

2–3 week-old female immunocompetent Balb/C mice (12–14 g) were infectedintraperitoneally with 3×10⁵ PFU/0.2 ml/mouse. Starting 6 hours afterthe infection, the mice were treated perorally with substance twicedaily (8.00 and 16.00 hours) over a period of 5 days. The dose was 3,10, 30 or 90 mg/kg of body weight, the administration volume 10 ml/kg ofbody weight. The substances were formulated in the form of a0.5%-strength Tylose suspension with 2% DMSO. In the period from 4–8days after infection, the placebo-treated control animals die. Theevaluation is carried out by the determination of the percentage ofsurviving animals after substance treatment in comparison with theplacebo-treated control group.

HCMV Xenograft Gelfoam® Model:

Animals:

3–4 week-old female immunodeficient mice (16–18 g), Fox Chase SCID orFox Chase SCID-NOD, were obtained from commercial breeders(Bomholtgaard, Jackson). The animals were kept in isolators understerile conditions (including litter and feed).

Virus Growth:

Human cytomegalovirus (HCMV), strain DavisSmith, was grown in vitro onhuman embryonic foreskin fibroblasts (NHDF cells). After infection ofthe NHDF cells with a multiplicity of infection (M.O.I) of 0.01, thevirus-infected cells were harvested 5–7 days later and stored at −140°C. with 10% DMSO in the presence of Minimal Essential Medium (MEM), 10%foetal calf serum (FCS). After serial dilution of the virus-infectedcells in steps of ten, the titre was determined on 24-well plates ofconfluent NHDF cells after vital staining with Neutral Red.

Preparation of the Sponges Transplantation, Treatment and Evaluation:

Collagen sponges 1×1×1 cm in size (Gelfoam®; from Peasel & Lorey, OrderNo. 407534; K. T. Chong et al., Abstracts of 39^(th) InterscienceConference on Antimicrobial Agents and Chemotherapy, 1999, p. 439) arefirstly wetted with phosphate-buffered saline (PBS), the included airbubbles are removed by degassing and they are then stored in MEM+10%FCS. 1×10⁶ virus-infected NHDF cells (infection with HCMV-DavisM.O.I=0.01) are detached 3 hours after infection and added dropwise to amoist sponge in 20 μl of MEM, 10% FCS. 12–13 hours later, the infectedsponges are incubated with 25 μl of PBS/0.1% BSA/1 mM DTT containing 5ng/μl of basic Fibroblast Growth Factor (bFGF). For transplantation, theimmunodeficient mice are anaesthetized with Avertin, the dorsal fur isremoved with the aid of a dry razor, the epidermis is opened 1–2 cm,relaxed and the moist sponges are transplanted under the dorsal skin.The operation wound is closed with tissue adhesive. 24 hours aftertransplantation, the mice were treated perorally with substance twicedaily over a period of 8 days (8.00 and 16.00 hours). The dose was 10 or30 mg/kg of body weight, the administration volume 10 ml/kg of bodyweight. The substances were formulated in the form of a 0.5% strengthTylose suspension with 2% DMSO. 10 days after transplantation and 16hours after the last substance administration, the animals were killedpainlessly and the sponge was removed. The virus-infected cells werereleased from the sponge by collagen digestion (330 U/1.5 ml) and storedat −140° C. in the presence of MEM, 10% foetal calf serum, 10% DMSO. Theevaluation is carried out after serial dilution of the virus-infectedcells in steps of ten by titre determination on 24-well plates ofconfluent NHDF cells after vital staining with Neutral Red. The numberof infectious virus particles after substance treatment was determinedin comparison with the placebo-treated control group.

The test described below serves for the investigation of the substancesaccording to the invention with a view to their side effect potentialwith respect to induction of cytochrome P450 enzymes.

Investigation of the Induction of Cytochrome P450 Enzymes in Human LiverCell Cultures:

Primary human hepatocytes were cultured for 8 days at a cell density of2.5×10⁵ cells between two layers of collagen in 24 well microtitreplates at 37° C. under 5% CO₂. The cell culture medium was changeddaily.

After 48 hours in culture, the hepatocytes were treated for 5 days induplicate with different concentrations of the test substances incomparison with the inductors rifampicin (50 μM) and phenobarbital (2mM). The final concentrations of the test substances were 0.1–10 μg/ml.

From the cell cultures, the inductive effect of the test substances onthe cytochrome (CYP) P450 enzymes 1A2, 2B6, 2C19 and 3A4 was determinedon day 8 by addition of the substrates 7-ethoxyresorufin (CYP1A2),[¹⁴C]S-mephenytoin (CYP2B6 and 2C19) and [¹⁴C]testosterone (CYP3A4). Theinductive potential of the test substances was determined from theenzyme activities thus measured of CYP1A2-, 2B6-, 2C19- and 3A4-treatedcells in comparison with untreated cells.

The new active compounds can be converted in a known manner into thecustomary formulations, such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, non-toxic, pharmaceutically suitable vehicles or solvents. Inthis connection, the therapeutically active compound should in each casebe present in a concentration of approximately 0.5 to 90% by weight ofthe total mixture, i.e. in amounts which are sufficient in order toachieve the dose range indicated.

The formulations are prepared, for example, by extending the activecompounds using solvents and/or vehicles, optionally using emulsifyingagents and/or dispersing agents, it being possible, for example, in thecase of the use of water as a diluent optionally to use organic solventsas auxiliary solvents.

Administration is carried out in a customary manner, preferably orally,parenterally or topically, in particular perlingually or intravenously.

For the case of parenteral administration, solutions of the activecompounds using suitable liquid carrier materials can be employed.

In general, it has proved advantageous in the case of intravenousadministration to administer amounts of approximately 0.001 to 10 mg/kg,preferably approximately 0.01 bis 5 mg/kg of body weight to achieveefficacious results, and in the case of oral administration the dose isapproximately 0.01 to 25 mg/kg, preferably 0.1 to 10 mg/kg of bodyweight.

In spite of this, it can optionally be necessary to depart from theamounts mentioned, namely depending on the body weight or on the type ofadministration route, on the individual behaviour towards themedicament, the manner of its formulation and the time or interval atwhich administration takes place. Thus in some cases it can be adequateto manage with less than the abovementioned minimum amount, while inother cases the upper limit mentioned must be exceeded. In the case ofthe administration of relatively large amounts, it may be advisable todivide these into a number of individual administrations over the courseof the day.

Abbreviations: Aloc-Cl allyl chloroformate DCM dichloromethane DICN,N′-diisopropylcarbodiimide DIEA diisopropylethylamine DMFdimethylformamide eq. equivalents HOAc acetic acid HOBthydroxybenzotriazole HONSu N-hydroxysuccinimide MTP microtitre plate PS-polystyrene resin- PyBOPbenzotriazolyl-N-oxy-tris(dimethylamino)phosphonium hexafluorophosphateRt reaction time RT room temperature TBABH tetrabutylammoniumborohydride TFA trifluoroacetic acid THF tetrahydrofuran TMOF trimethylorthoformateGeneral Working Procedure for the Reaction of Compounds of the Formula[A-1] with Compounds of the Formula [A-2] (GWP 1):

1.0 eq of [A-1] is dissolved in dioxane (0.2 M solution), treated with2.5 eq. of pyridine, the solution is cooled to 5° C. and then 1.1 eq. of[A-2], in which Q preferably represents chlorine, is added dropwise as a1.0 M solution. The batch is stirred further at 5° C. for 30 min, thenthe cooling is removed and stirring is continued at room temperature for16 h. The batch is added to H₂O, and the precipitated product isfiltered off with suction, washed with H₂O and dried in a high vacuum.

General Working Procedure for the Hydrogenation of Compounds of theFormula [A-3] (GWP 2):

0.14 mol of the compounds [A-3] is dissolved in 500 ml of DMF or ethanoland treated under argon with a suspension of 6.0 g of 10% strength Pd—C.It is then hydrogenated at a hydrogen pressure of 3 bar. As soon as theconversion is complete (TLC or HPLC checking), the Pd—C catalyst isfiltered off and the solvent is removed in vacuo. The crude products ofthe general formula [B-1] are reacted further without furtherpurification.

General Working Procedure for the Sulphonylation of the Compounds of theGeneral Formula [B-1] (GWP 3):

Under argon, 1.0 eq. of the compounds [B-1] are dissolved in dioxane(0.2 M solution) and treated with 2.5 eq. of pyridine. After the mixturehad been stirred at room temperature for 30 min, 1.1 eq. of thecompounds of the general formula [C-1], in which Z preferably representschlorine, dissolved in dioxane (1.0 M solution) are added and themixture is stirred at room temperature for 16 h. The solution is thenadded to H₂O and extracted three times with DCM. The organic phase iswashed with satd. NaHCO₃ solution, dried over Na₂SO₄, filtered and thesolvent is removed in vacuo. The residue [C-2] is dried in a high vacuumand then reacted further without further purification.

General Working Procedure for the Synthesis of Compounds of the GeneralFormula [D-1] from Compounds of the General Formula [C-2] (GWP 4):

The compounds of the formula [C-2] (1.0 eq.) are dissolved in ethanol(0.1 M solution), the solution is treated with hydroxylaminehydrochloride (1.5 eq.) and triethylamine (1.6 eq.), then heated underreflux for 4 h and stirring is continued at room temperature for 16 h.The solvent is removed in vacuo, the residue is taken up in ethylacetate and extracted 3× with water, the organic phase is dried overMgSO₄, filtered and freed of the solvent in vacuo. The residue [D-1] isdried in a high vacuum.

General Working Procedure for the Reaction of the Compounds of theGeneral Formula [D-1] with Compounds [E-1] (GWP 5):

1.0 eq. of the compounds of the general formula [D-1], 1.05 eq. ofcarboxylic acid [E-1] and 1.1 eq. PyBOP are introduced in THF (0.1 Msolution), the suspension is treated with 1.1 eq. ofN,N-diisopropylethylamine and the resulting solution is stirred at roomtemperature for 16 h. The batch is then diluted with 10 ml of DCM andextracted once each with 1 N HCl, satd. NaHCO₃ solution and satd. NaClsolution. The organic phase is dried over Na₂SO₄, filtered and thesolvent is removed in vacuo. The crude product is directly reactedfurther.

General Working Procedure for the Synthesis of a 1,2,4-oxadiazole fromthe Crude Product (GWP 6) Obtained According to GWP 5:

1.0 mmol of crude product obtained according to GWP 5 is taken up in 10ml of DMF and the solution is heated to 110° C. As soon as theconversion is complete (TLC or HPLC checking, about 2–16 h), the batchis diluted with DCM and extracted twice with H₂O. The combined aqueousphases are extracted twice with DCM, the organic phases are combined anddried over Na₂SO₄, filtered and the solvent is removed in vacuo. Thecompounds of the general formula (I) thus obtained are purified bychromatography on silica gel (cyclohexane/ethyl acetate) or bypreparative HPLC.

General Working Procedure for the Removal of a Boc Protective Group (GWP7):

1.0 mmol des Boc-protected amine are taken up in 10 ml of a mixture ofTFA/CH₂Cl₂ or TFA/dioxane (1:1 v/v), and the solution is stirred at RT.As soon as the conversion is complete (about 45 min), the solvent isremoved in vacuo, the residue is taken up in DCM and the mixture isextracted twice with satd. NaHCO₃ solution. The combined aqueous phasesare extracted twice with CH₂Cl₂, the organic phases are combined anddried over Na₂SO₄, filtered and the solvent is removed in vacuo. Theproduct is purified by chromatography on silica gel (cyclohexane/ethylacetate) or by preparative HPLC.

General Working Procedures for the Syntheses Using Polymeric Supports:

General Working Procedure for the Synthesis of the 1,3,4-oxadiazolesAccording to Scheme 4:

The reactions according to Scheme 4 were carried out on a polymericsupport using the IRORI system according to the “Split & Mix” methodfamiliar to the solid-phase chemist with 4 carboxylic acid chlorides, 24carboxylic acids and both meta- and para-isomers of the phenylenediamineor sulphonyl chloride. In this connection, the first two stages werecarried out in a flask, the other stages in the IRORI minikans (100 mgof resin per Kan).

Synthesis of the Starting Resins (I) and (II) for the Syntheses on thePolymeric Support According to Scheme 4:

Reductive Amination of formyl Resin (from Nova Biochem, 0.78 mmol/g):

The formyl resin (1.0 eq.) is suspended in TMOF/DMF (100 ml per 12.5 gof resin) in a flask and treated with the diamine (6.0 eq.). Thesuspension is shaken at 40° C. for 16 h and then treated with a freshlyprepared solution of TBABH (4.0 eq.) and HOAc (16.0 eq.) in DMF. After 8h at RT, the solvent is filtered off and the resin is treated again withthe reduction solution. After a further 16 h at RT, the solvent isfiltered off with suction and the resin (I) is washed 2× in each casewith 200 ml each of 50% strength HOAc, DMF, THF and DCM and dried in ahigh vacuum.

Sulphonylation of Polymer-Bound Phenylendiamine:

The resin (I) (1.0 eq.) is taken up in THF and treated with thesulphonyl chloride (1.5 eq.). The suspension is shaken at RT for 16 hand the solvent is filtered off with suction. The resin (II) is thenwashed 2× each with 100 ml each of 50% strength HOAc, DMF, THF and DCMand dried in a high vacuum.

Resin Preparation for the IRORI System:

The resins of type II are divided as a suspension (per 3.0 g of resin:30 ml DMF/DCM 2:1 v/v) into 96 minikans each (1 ml of suspension perKan), washed with DCM three times in each case and the Kans are dried invacuo.

Reaction Sequence (IRORI):

Acylation Using Acid Chlorides:

The Kans are sorted, taken up in THF and treated with 5.0 eq. of DIEAand 5.0 eq. of acid chloride, briefly evacuated, and shaken at RT for 3h. The reaction solutions are then separated off, and the Kans arecombined and washed (2× each 50% strength HOAc, DMF, THF, DCM).

Hydrazide Synthesis:

The combined Kans are taken up in a mixture of 2 N NaOH/MeOH/THF (5:7:15v/v), briefly evacuated, and stirred at 50° C. for 5 h. The Kans arethen washed (2× each 50% strength HOAc, DMF, THF, DCM) and dried invacuo. The Kans are then taken up using THF, treated with 5 eq. of DICand 10 eq. of HONSu and shaken at RT for 3 h. The mixture is filteredoff, washed 2× with THF and then taken up again using THF and treatedwith 3 eq. of hydrazine hydrate. After a further 3 h at RT, the mixtureis filtered off with suction and the Kans are washed with 2× each of 50%strength HOAc, DMF, THF, DCM.

Acylation with Carboxylic Acids/DIC/HOBt:

The carboxylic acids (3 eq.) are treated with 3 eq. of DIC, 6 eq. ofDIEA and 6 eq. of HOBt in THF. After activation at RT for 60 min, thesolution is added to the previously sorted Kans and shaken at RT for 16h. The Kans are then combined, washed (2× each 50% strength HOAc, DMF,THF, DCM) and dried in vacuo.

Cyclization to the 1,3,4-oxadiazole:

The combined Kans are taken up in DMF, treated with DIC (10 eq.),briefly evacuated and stirred at 110° C. for 48 h. The Kans are thenwashed (2× each 50% strength HOAc, DMF, THF, DCM) and dried in vacuo.

Removal from the Polymeric Support:

After sorting into IRORI removal blocks, the Kans are cut up, the resinis divided in FlexChem blocks and the products are removed using 1.0 mleach of TFA/DCM (1:1 v/v) for 45 min at RT in a Deep-Well MTP. The resinis subsequently washed with 1 ml of DCM and the solvent is evaporated.

Starting Compounds:

EXAMPLE I 1-Methyl-N-(3-nitrophenyl)-cyclopropanamide

This compound is prepared from 80.0 g of 3-nitroaniline according to GWP1.

Yield: 107 g (81% of theory)

EXAMPLE II 3-Fluoro-2,2-dimethyl-N-(3-aminophenyl)-propanamide

This compound is prepared from 3-nitroaniline without purification ofthe intermediate stage according to GWP 1 and GWP 2.

Yield: 85% of theory (over 2 stages)

EXAMPLE III 1-Methyl-N-(3-aminophenyl)-cyclopropanamide

This compound is prepared from 107 g of the compound from Example Iaccording to GWP 2.

Yield: 80 g (87% of theory)

EXAMPLE IV3-Fluoro-2,2-dimethyl-N-(3-{[(4-methylphenyl)sulphonyl]amino}phenyl)-propanamide

This compound is prepared from 18.68 g of the compound from Example IIaccording to GWP 3.

Yield: 19.96 g (78% of theory)

EXAMPLE VN-{3-[({4-[Amino(hydroxyimino)methyl]phenyl}(sulphonyl)amino]phenyl}-3-fluoro-2,2-dimethylpropanamide

This compound is prepared from 10.0 g of the compound from Example IVaccording to GWP 3.

Yield: 10.5 g (97% of theory)

EXAMPLE VIN-(3-{[(4-Phenyl)sulphonyl]amino}phenyl)-1-methylcyclopropanecarboxamide

This compound is prepared from 80.0 g of the compound from Example IIIaccording to GWP 3.

Yield: 159 g of crude product (>100% of theory)

EXAMPLE VIIN-{3-[({4-[Amino(hydroxyimino)methyl]phenyl}(sulphonyl)amino]phenyl}-1-methylcyclopropanecarboxamide

This compound is prepared from 158 g of the compound from Example VIaccording to GWP 3.

Yield: 148 g (83% of theory)

WORKING EXAMPLES

The working examples for 3-linked 1,2,4-oxadiazoles mentioned below wereprepared from the compounds of the type Example V according to GWP 5,GWP 6 and GWP 7.

EXAMPLE 1N-(4-{[(3-{5-[(1S)-1,5-Diaminopentyl]-1,2,4-oxadiazol-3-yl}phenyl)sulphonyl]-amino}(phenyl)-1-methylcyclopropanecarboxamide

100 mg (0.257 mmol) of the amidoxime, which is prepared analogously toExamples IV and V, 93.6 mg (0.27 mmol) of Boc-Lys(Boc)-OH and 147 mg(0.27 mmol) of PyBOP are introduced into 3 ml of THF, the suspension istreated at room temperature with 36.6 mg (56.66 mmol) ofN,N-Diisopropylethylamine and the resulting clear solution is stirred atroom temperature for 16 h. The batch is then diluted with 15 ml ofCH₂Cl₂ and extracted once each with 10 ml each of 1N HCl, satd. NaHCO₃solution and satd. NaCl solution. The organic phase is dried overNa₂SO₄, filtered and the solvent is removed in vacuo. The crude product(184 mg) is taken up in 7 ml of DMF and the solution is stirred at 110°C. for 2.5 h. The batch is then diluted with 15 ml of CH₂Cl₂ and theorganic phase is extracted twice with 10 ml each of H₂O. The combinedaqueous phases are extracted twice with 10 ml each of CH₂Cl₂, theorganic phases are combined and dried over Na₂SO₄, filtered and thesolvent is removed in vacuo. The product is purified by chromatographyon silica gel 60 using cyclohexane/ethyl acetate 1:1 v/v. Yield: 141 mg(79%), white solid.

For removal of the Boc protective groups, the product is dissolved in 5ml of a TFA/DCM solution (1:1 v/v) and the reaction mixture is stirredat RT for 30 min. The solvent is then removed in vacuo, the residue istaken up in 3 ml of 1N NaOH, adjusted to pH=9 using 1N HCl and the crudeproduct is added to a chromatography column containing a weakly acidicion exchanger (Amberlite IRC50, 20–50 mesh), the column is washed withMeOH/H₂O mixtures (1:9→3:6) and the product is then eluted using 5% NH₃in MeOH/H₂O (5:95 v/v). The solvent is removed in vacuo and the residueis taken up in 1 ml of H₂O and lyophilized.

Yield: 15.7 mg (18%), white lyophilizate. ¹H-NMR (200 MHz, DMSO):δ=0.47–0.60 (m, 2 H), 0.90–1.01 (m, 2 H), 1.22–1.53 (m, 4 H), 1.36 (s, 3H), 1.65–1.90 (m, 2 H), 2.63 (t, 2 H), 4.12 (t, 1 H), 6.80 (d, 2 H),7.21 (d, 2 H), 7.59 (t, 1 H), 7.84 (d, 1 H), 8.04 (d, 1 H), 8.33 (s, 1H), 8.88 (s, 1 H).

EXAMPLE 2N-(3-{[(4-{5-[(1S)-1-Amino-2-methylpropyl]-1,2,4-oxadiazol-3-yl}phenyl)sulphonyl]amino}phenyl)-1-methylcyclopropanecarboxamide

183 mg (1.42 mmol) of N,N-diisopropylethylamine, 294 mg (1.35 mmol) ofBoc-Val-OH and 737 mg (1.42 mmol) of PyBOP are introduced into 15 ml ofTHF, stirred at room temperature for 30 min, then treated with 500 mg(1.29 mmol) of the amidoxime and the solution is stirred at roomtemperature for 16 h. The batch is then diluted with 30 ml of CH₂Cl₂ andextracted once each with 20 ml each of 1N HCl, satd. NaHCO₃ solution andsatd. NaCl solution. The organic phase is dried over Na₂SO₄, filteredand the solvent is removed in vacuo. The crude product (1.18 g) is takenup in 45 ml of DMF and the solution is stirred at 110° C. for 8 h. Thesolvent is then removed in vacuo, the residue is dissolved in 20 ml of aTFA/DCM solution (1:1 v/v) and the reaction mixture is stirred at RT for45 min. The solvent is then removed in vacuo, the residue is taken up in30 ml of DCM and the organic phase is extracted twice with 30 ml each ofH₂O. The combined aqueous phases are extracted twice with 30 ml each ofCH₂Cl₂, and the organic phases are combined and dried over Na₂SO₄,filtered and the solvent is removed in vacuo. The product is purified bypreparative HPLC (CromSil C18, 250×30, flow 50 ml/min, running time: 38min, detection at 210 nm, gradient 10% ACN (3 min)→90% ACN (31 min)→90%ACN (34 min)→10% ACN (34.01 min)).

Yield: 394 mg (65%), white solid. ¹H-NMR (300 MHz, DMSO): δ=0.56–0.62(m, 2 H), 0.87 (d, 3 H), 0.94 (d, 3 H), 1.01–1.08 (m, 2 H), 1.96–2.12(m, 1 H), 3.95 (d, 1 H), 6.76 (d, 1 H), 7.11 (t, 1 H), 7.27 (d, 2 H),7.56 (s, 1 H), 7.94 (d, 2 H), 8.16 (d, 2 H), 9.17 (s, 1 H)

EXAMPLE 3N-(3-{[(4-{5-[(1S)-1-Amino-2-methylpropyl]-1,2,4-oxadiazol-3-yl}phenyl)sulphonyl]amino}phenyl)-3-fluoro-2,2-dimethylpropanamide

522 mg (4.04 mmol) of N,N-diisopropylethylamine, 838 mg (3.86 mmol) ofBoc-Val-OH and 2.1 g (4.04 mmol) of PyBOP are introduced into 50 ml ofTHF, stirred at room temperature for 45 min, then treated with 1.5 g(3.67 mmol) of the amidoxime and the solution is stirred at roomtemperature for 16 h. The batch is then concentrated in vacuo, theresidue is taken up using 200 ml of EtOAc and extracted three times withH₂O. The organic phase is dried over Na₂SO₄, filtered and the solvent isremoved in vacuo. The crude product (1.8 g) is taken up in 45 ml of DMFand the solution is stirred at 110° C. for 4 h. The batch is thendiluted with 100 ml of EtOAc and extracted three times with H₂O. Theorganic phase is dried over Na₂SO₄, filtered and the solvent is removedin vacuo. The product is purified by chromatography on silica gel 60using cyclohexane/ethyl acetate 1:1 v/v. Yield: 1498 mg (86%), whitesolid.

For removal of the Boc protective groups, the product is dissolved in 10ml of dioxane and treated with 10 ml of 4N HCl in dioxane. After 2h at60° C., the solvent is removed in vacuo, the residue is treated with 100ml of satd. NaHCO₃ solution and extracted twice with 200 ml each ofEtOAc. The organic phase is dried over Na₂SO₄ and the solvent is removedin vacuo. The product is dried in a high vacuum and obtainedanalytically pure.

Yield: 910 mg (73%), white solid ¹H-NMR (300 MHz, DMSO): δ=0.86 (d, 3H), 0.93 (d, 3 H), 1.20 (s, 6 H), 1.96–2.11 (m, 1 H), 3.94 (d, 1 H),4.47 (d, 2 H), 6.89 (d, 1 H), 7.13 (t, 1 H), 7.30 (d, 1 H), 7.56 (s, 1H), 7.94 (d, 2 H), 8.26 (d, 2 H), 9.34 (s, 1 H).

HPLC HPLC Rt method/ m/z fnd Example Structure MW [min] instrument (M +H)⁺ 4

485.47 4.03 1 490 5

518.61 2.61 3 519 6

728.65 3.59 1 499 7

483.59 2.765 2 484 8

483.59 1.872 2 484 9

483.59 1.879 2 484 10

469.56 1.841 2 470 11

518.61 3.71 1 519 12

518.67 3.76 1 519 13

497.62 3.15 3 498.1 14

517.61 2.96 4 518 15

518.61 3.76 1 519 16

518.80 2.25 4 519 17

455.54 1.706 2 455 18

497.62 3.023 3 498 19

483.59 2.84 4 484 20

518.00 4.26 1 518 21

553.70 3.24 3 564 22

537.61 4.19 1 630 23

503.58 4.06 1 504 24

503.58 1.897 2 504 25

484.58 2.088 2 485 26

483.59 2.744 2 484 27

441.41 2.49 3 442 28

453.52 2.5 3 454 29

518.62 3.75 1 519 30

487.55 4.05 1 488 31

516.60 1.507 2 519 32

483.59 4.17 1 484 33

518.00 4.17 1 518 34

504.58 3.68 1 505 35

441.51 3.89 1 442 36

503.60 4.19 1 504 37

503.60 4.13 1 504 38

483.60 4.15 1 484 39

484.58 1.986 2 485 40

455.54 2.52 2 456 41

504.58 3.65 1 605 42

489.56 4.07 1 470 43

503.60 4.78 1 504 44

517.62 4.24 1 518 45

517.61 4.2 1 518 46

503.60 4.17 1 504 47

480.58 3.99 1 470 48

489.57 4.02 1 490 49

469.56 3.86 1 470 50

483.59 2.799 2 484 51

537.61 4.14 1 538 52

453.52 3.81 1 454 53

484.58 2.049 2 485 54

503.60 4.22 1 504 55

523.59 4.06 1 524 56

503.60 3.99 1 504 57

455.64 2.505 2 456 58

503.60 2.765 2 604 59

427.48 2.417 2 428 60

451.52 3.82 1 482 61

503.60 4.18 1 504 62

483.59 2.749 2 484 63

503.60 2.828 2 604 64

475.64 3.88 1 476 65

461.52 3.84 1 462 66

469.56 2.64 2 470 67

473.53 3.69 1 474 68

483.59 2.85 4 484.6 69

455.54 2.548 2 456 70

489.47 3.98 1 490 71

504.58 3.85 1 505 72

484.58 1.981 2 485 73

503.60 4.04 1 504 74

504.58 3.79 1 505 75

517.52 4.19 1 518 76

489.57 4.06 1 490 77

501.58 3.93 1 502 78

503.60 4.1 1 504 79

489.57 3.98 1 490 80

515.60 3.78 1 519 81

483.59 2.82 4 484 82

469.56 2.522 2 470 83

518.00 4.2 1 518 84

504.58 2.053 2 505 85

447.49 3.78 1 448 86

483.59 2.84 4 484 87

427.48 2.428 2 428 88

489.57 2.58 2 490 89

501.58 3.91 1 502 90

447.49 3.78 1 448 91

455.54 2.547 2 456 92

504.58 2.017 2 505 93

490.56 3.72 1 491 94

518.81 3.83 1 519 95

427.48 2.407 2 428 96

503.60 2.8 4 504 97

459.58 2.512 2 470 98

451.52 2.58 4 462 99

447.49 2.431 2 448 100

501.58 3.94 1 502 101

427.48 2.393 2 428 102

503.60 2.77 4 504.5 103

475.54 2.57 2 476 104

447.49 2.409 2 448 105

483.59 2.82 4 484 106

481.52 2.488 2 462

TABLE 2 The compounds mentioned in the working examples and tables werecharacterized using the LC-MS and HPLC processes described below: Method1: Column: Kromasil C18 60*2, L-R temperature: 30° C., flow = 0.75 mlmin⁻¹, eluent: A = 0.005 M HClO₄, B = CH₃CN, gradient: → 0.5 min 98% A →4.5 min 10% A → 6.5 min 10% A Method 2: Column: Symmetry C18 2.1 × 150mm, column oven: 50° C., flow = 0.9 ml min⁻¹, eluent: A = 0.3 g 30%strength HCl/1 water, B = CH₃CN, gradient: 0.0 min 90% A → 3.0 min 10% A→ 6.0 min 10% A Method 3: HP1100, column: LiChroCart 75-5 LiChrospher100 RP-18 5 μm, column oven: 40° C., flow = 2.5 ml min⁻¹, eluent: A =water containing 0.05% of TFA, B = CH₃CN containing 0.05% of TFA,gradient: 0.0 min 90% A → 0.05 min 90% A → 5.0 min 5% A → 7.0 min 5% A →7.05 min 90% A → 8.0 min 90% A Method 4: LC-MS: MHZ-2P, instrumentMicromass Platform LCZ Column: Symmetry C18 50 mm × 2.1 mm, 3.5 μm,temperature: 40° C., flow = 0.5 ml min⁻¹, eluent A = CH₃CN + 0.1% offormic acid, eluent B = water + 0.1% of formic acid, gradient: 0.0 min10% A → 4 min 90% A → 6 min 90% A

1. A compound of the general formula (I)

in which R² and R³ are identical or different and represent hydrogen,hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,(C₁–C₆)-alkyl, (C₁–C₆)-alkoxy or a group of the formula

 in which R⁵, R⁶ and R⁷ are identical or different and in each caserepresent hydrogen or (C₁–C₆)-alkyl, which for its part can besubstituted by one or two substituents selected from the groupconsisting of hydroxyl, halogen, cyano, trifluoromethyl andtrifluoromethoxy, A represents a five- or six-membered heteroaryl linkedvia a C atom to the adjacent phenyl ring, R¹ represents the radical

 in which R¹¹ represents the side group of an amino acid, and the aminogroup in R¹ can optionally be mono- or polysubstituted by (C₁–C₆)alkyl,alkylcarbonyl, or phenyl, or R¹ represents a straight-chain or branched(C₁–C₅)-alkyl radical, which for its part can be substituted by one ormore groups selected from phenyl, piperidinyl, pyridinyl, thiazolyl,thienyl,

 or a group

 in which R¹² and R¹³ are identical or different and can representhydrogen, (C₁–C₆)alkyl, alkylcarbonyl, an amino protective group, orphenyl, or R¹ represents a radical

 or R¹ represents a straight-chain or branched (C₁–C₅)-alkyl radical,which for its part is substituted by a group

 in which R¹⁴, R¹⁵, R¹⁶ are identical or different and representhydrogen or (C₁–C₆)alkyl  and n can assume the values 2 or 3, or R¹represents piperidinyl or the radical

 in which R¹² and R¹³ have the meaning indicated above, n represents anumber from 1 to 4 and the ring can be up to trisubstituted in anidentical or different manner by halogen, (C₁–C₆)-alkyl,halogeno-(C₁–C₆)-alkyl, amino, or hydroxyl, R⁴ represents tert-butyl,which is optionally up to trisubstituted, in an identical or differentmanner, by hydroxyl, fluorine or chlorine, or  represents cyclopropyl orcyclobutyl, which are mono- to trisubstituted in an identical orindependent manner by halogen or (C₁–C₆)-alkyl, (C₁–C₆)-alkyl optionallybeing substituted by hydroxyl, fluorine or chlorine, and in which Xrepresents oxygen or sulphur, and in which nitrogen-containingheterocycles can also be present as N-oxides, or a tautomer,stereoisomer, or mixture of stereoisomers of said compound, or apharmacologically tolerable salt of said compound, tautomer,stereoisomer, or mixture of stereoisomers.
 2. The compound of thegeneral formula (I) according to claim 1, in which R² and R³ areidentical or different and represent hydrogen or halogen, A representsthe radical (A-I)

which is linked via one of the carbon atoms of positions 3 or 5 to theadjacent phenyl ring, and in which Y represents oxygen, or A representsthe radical (A-II)

 which is linked via one of the carbon atoms of positions 2 or 5 to theadjacent phenyl ring,  and in which Y represents oxygen, R¹ representsthe radical

 in which R¹¹ represents the side group of an amino acid, and the aminogroup in R¹ can optionally be mono- or polysubstituted by (C₁–C₆)-alkyl,alkylcarbonyl, an amino protective group, or phenyl, or R¹ represents astraight-chain or branched (C₁–C₅)-alkyl radical, which for its part canbe substituted by one or more groups selected from phenyl, piperidinyl,pyridinyl, thiazolyl, thienyl,

 a group

 in which R¹² and R¹³ are identical or different and can representhydrogen, (C₁–C₆)-alkyl, alkylcarbonyl, an amino protective group, orphenyl, or R¹ represents a straight-chain or branched (C₁–C₅)-alkylradical, which for its part is substituted by a group

 in which R¹⁴, R¹⁵, R¹⁶ are identical or different and representhydrogen or methyl and n can assume the values 2 or 3, or R¹ representspiperidin-3-yl or the radical

R⁴ represents tert-butyl, which is optionally up to trisubstituted, inan identical or different manner, by hydroxyl, fluorine or chlorine, or represents cyclopropyl or cyclobutyl, which is substituted in theα-position to the carbonyl group or thiocarbonyl group by methyl, whichfor its part is optionally substituted by hydroxyl, fluorine orchlorine, and in which X represents oxygen, and in whichnitrogen-containing heterocycles can also be present as N-oxides, or atautomer, stereoisomer or mixture of stereoisomers of said compound, ora pharmacologically tolerable salt of said compound tautomer,stereoisomer, or mixture of stereoisomers.
 3. The compound of thegeneral formula (I) according to claim 1, in which R² and R³ representhydrogen, A represents one of the radicals

R¹ represents the radical

 in which R¹¹ represents the side group of an amino acid, and the aminogroup in R¹ can optionally be mono- or polysubstituted by methyl,alkylcarbonyl, an amino protective group, or phenyl, or R¹ represents astraight-chain or branched (C₁–C₅)-alkyl radical, which for its part canbe substituted by one or more groups selected from phenyl, piperidinyl,pyridinyl, thiazolyl, thienyl,

 or a group

 in which R¹² and R¹³ are identical or different and can representhydrogen, methyl, alkylcarbonyl, an amino protective group, or phenyl,or R¹ represents a straight-chain or branched (C₁–C₅) alkyl radical,which for its part is substituted by a group

 in which R¹⁴, R¹⁵, R¹⁶ are identical or different and representhydrogen or methyl and n can assume the values 2 or 3, or R¹ representspiperidin-3-yl or the radical

R⁴ represents tert-butyl, which is optionally up to trisubstituted, inan identical or different manner, by hydroxyl, fluorine or chlorine, or represents cyclopropyl or cyclobutyl, which is substituted in theα-position to the carbonyl group or thiocarbonyl group by methyl, whichfor its part is optionally substituted by hydroxyl, fluorine orchlorine, and in which X represents oxygen, and in whichnitrogen-containing heterocycles can also be present as N-oxides, or atautomer, stereoisomer, or mixture of stereoisomers of said compound ora pharmacologically tolerable salt of said compound, tautomer,stereoisomer, or mixture of stereoisomers.
 4. The compound of thegeneral formula (I) according to claim 1, in which R⁴ represents one ofthe radicals


5. A compound of the general formula (Ia)

in which R¹, R², R³, R⁴, A and X have the meanings indicated above inclaim
 1. 6. The compound of the general formula (I) according to claim1, in which A represents a 3-linked 1,2,4-oxadiazole.
 7. The compound ofthe general formula (I) according to claim 1, which is selected from thegroup consisting of the following compounds:


8. A process for the preparation of compounds of the general formula (I)according to claim 1, in which a compound of the general formula (D-1)

in which X, R², R³ and R⁴ have one of the meanings indicated above inclaim 1, is acylated with a carboxylic acid of the general formula (E-1)R¹—COOH  (E-1) in which R¹ has the meaning indicated above in claim 1and free amino groups contained in R¹ are present protected by aminoprotective groups, in the presence of a condensing agent and of a base,and the acylated amidoxime is cyclized to the 1,2,4-oxadiazole.
 9. Aprocess for the preparation of compounds of the general formula (I)according to claim 1, in which a compound of the general formula (G-2)

in which R¹, R², R³, R⁴ and X have the meaning indicated above in claim1, are cyclized.
 10. A compound of the general formula (D-1)

in which R², R³, R⁴ and X have the meanings indicated in claim
 1. 11. Acompound of the general formula (G-2)

in which R¹, R², R³, R⁴ and X have the meanings indicated in claim 1.12. A pharmaceutical composition comprising a compound of the generalformula (I) according to any one of claims 1 to
 7. 13. A method for thetreatment of cytomegalovirus infection, comprising administering aneffective amount of a compound of claim 1.